Audacious (Winter 2004 Trust Magazine article)

He is also single-minded, brilliant, and hard working, all of which helped carry the Pew Scholar in the Biomedical Sciences (Class of '92) to the 2003 Nobel Prize in Chemistry. The award recognized him for identifying the atomic structures of ion channels, tiny pores in the membranes of cells that control the electrical impulses behind every movement, every sensation, and every thought.

But it is MacKinnon's audacity that sets him apart.

“Every scientist knows in his field what the big barriers are to further progress,” says Christopher Miller, Ph.D., a professor of biochemistry at Brandeis University and investigator with the Howard Hughes Medical Institute. Miller is also a member of the Pew Scholars national advisory committee and a former mentor to MacKinnon. “Any scientist contemplating a project to get over one of those barriers does a calculation of risk: Is it likely to work? What would I have to do to make it work? Rod did that calculation in this case, but then said to hell with it.

“He committed himself totally, in his resources and his attention, to the problem. And that was very risky, because no one knew how to get over that wall. And everybody knew it was an enormously difficult thing to do. What Rod did is he just bet the farm.”

MacKinnon's willingness to make bold moves had shown itself at least once earlier, a decade before he undertook the experiments that would lead to the Nobel.

In the mid-1980s, nearing the end of four years of medical school at Tufts University and a three-year residency at Beth Israel Hospital in Boston, MacKinnon began to doubt his career course, since, he was discovering, he preferred basic science.

As he explained to oral historian Andrea J. Maestrejuan in 1997, “It's as if you use a different part of your brain in medicine than you do in solving problems in science, and it was something I really missed.”

And so, recalling happier days doing science as an undergraduate in Miller's lab at Brandeis, MacKinnon abandoned medicine at age 30 and joined Miller's team as a postdoctoral fellow. There he began the study of ion channels. Surrounded by colleagues who had been learning science while he had been in medical school, he worked to make up for lost time. He studied intensively and discovered a powerful and satisfying capacity for self-teaching.

The defining expression of MacKinnon's intrepid nature, however, would come in a career shift that set the stage for his Nobel-winning investigations.

The research in Miller's lab had led to a job as an assistant professor at Harvard Medical School in 1989, and on the strength of the work he was doing during this period, he was selected as a Pew Scholar. The program offers flexible funding--$50,000 a year for four years at that time--to promising young investigators to encourage a risk-taking approach to difficult questions.

“For a young scientist, it was quite a bit of money to let me do some work that I otherwise couldn't do,” MacKinnon says. “But the biggest way it helped is that I know so many scientists from the [annual] meetings, people who are now lifelong colleagues. It's really enriched my scientific and intellectual life to have been part of the Pew family.”

With the Pew support, MacKinnon learned to mutate, in controlled ways, the genes coding for ion-channel proteins and then to test the mutant channels by measuring their electrical activity. Working back and forth primarily between these two techniques--mutate, test, mutate, test--he inferred a great deal about the structure and function of channels. By 1996, he was a full professor at Harvard, highly regarded by his peers--but increasingly dissatisfied.

The tools at hand were insufficient to answer the question that had come to dominate the field. How, he and others wanted to know, did the potassium ion channel selectively admit potassium ions--at high rates and in enormous numbers--while refusing entry to sodium ions, which carried the same electrical charge and were much smaller?

To understand the mechanism of the so-called “selectivity filter,” MacKinnon realized he would need to see the channel. And the only way to do that was through X-ray crystallography, a mainstay technique in the field of structural biology: A molecule is purified in quantity and crystallized. X-rays aimed at the crystals diffract in patterns that, with the aid of computers, can be used to construct an atomic portrait of the molecule.

Structural biologists had shied away from trying to solve the atomic structure of ion channels, and with good reasons. Chief among them was the fact that ion channels normally reside in the oily membranes of cells, making them a class of biological proteins that are uniquely difficult to crystallize.

Structural biology is also a notoriously demanding discipline, and it was a field in which MacKinnon had no background. So he began to read and to talk to structural biologists. Some were encouraging, but warned him that the project he was considering could easily take a decade or more to complete--if, indeed, it could be done at all.

At this point, a chance conversation at the annual meeting of the Pew Scholars Program lent a guiding hand. Every March, the current Pew Scholars hold a professional meeting to discuss their research with each other. Since the Scholars represent many disciplines, the meetings have stimulated fresh thinking and, pointedly, innovative exchanges.

“There are cross-sector collaborations involving people who met in the Scholars Program that have been going on now for 10 or 12 years,” says Edward H. O'Neil, Ph.D., executive director of the Program and director of the Center for the Health Professions at the University of California at San Francisco, where the program is housed. “Together, they're inventing whole new lines of investigation that then become the focus of their work.”

At the 1995 meeting, MacKinnon discussed his problem with Torsten Wiesel, M.D., chair of the Pew Scholars national advisory committee. Wiesel, the 1981 Nobel Prize winner in physiology or medicine and then president of Rockefeller University, listened thoughtfully. Then he invited MacKinnon to come to Rockefeller to give a talk on his research to the faculty. MacKinnon accepted and traveled to New York not long afterward.

“I stepped out of the cab [at Rockefeller] and looked around,” MacKinnon recalled to Maestrejuan in his oral history. “Something appealed to me instantly.”

He met a number of scientists with whom he connected well, including Pew Scholar Seth A. Darst, Ph.D. ('95), and shortly thereafter decided to move to Rockefeller.

MacKinnon established the Laboratory of Molecular Neurobiology and Biophysics at Rockefeller in 1996 with two other people, Alice Lee, who is his wife, and Declan Doyle, a postdoctoral fellow. In 1997, MacKinnon also became a Howard Hughes Medical Institute investigator at Rockefeller. Frederick J. Sigworth, Ph.D., joined the new MacKinnon lab for six months that year while on sabbatical from Yale University, where he is a professor of physiology. MacKinnon and his coworkers were immersed in efforts to crystallize the KcsA potassium channel from a bacterium called Streptomyces lividans.

“It was a dedicated and incredibly hard-working group,” Sigworth says. “They were all working 12- and 16-hour days. Rod is a very intense person, a very focused person. He was not going to be sidetracked.”

“I love learning new things, and I have a lot of confidence in myself, actually,” MacKinnon says. “And I desperately wanted to see the atomic structure of a potassium channel.”

Incredibly, it took MacKinnon's team less than two years to crystallize the KcsA channel and analyze its atomic structure, which appeared on the cover of the journal Science on April 3, 1998.

The structure revealed four identical subunits forming the cylinder of the ion channel. Each of the four subunits presents a row of five oxygen atoms spaced out along the pore lining. Thus an ion passing through the pore encounters five subsequent rings of four oxygen atoms, in which the four oxygen atoms are held at precise distances from each other by the overall structure of the channel. Those distances are the key to the selectivity filter.

To maintain a neutral electrical state, positively charged potassium ions outside the cell surround themselves with eight water molecules, using the negatively charged oxygen atoms in the water to balance their electrical needs. The four oxygen atoms in each ring lining the ion channel correspond exactly to the dimensions of a potassium ion, and the position between any two rings provides the same level of electrostatic comfort for the ions that they would have in free solution, nestled into a complex of eight oxygen atoms. So the ions enter the channel without resistance and pass readily through the rings. The four resting positions in the five-ring filter also give the positively charged potassium ions, which repel each other, a way to avoid each other. Ions and water molecules alternate in the four positions, so that only two ions are in the filter at any given moment, always with a water-molecule buffer between them.

And what of the sodium ions? With the same electrical charge as potassium ions, why don't they enter the filter? The answer is that sodium ions are smaller than potassium ions, so that the distances between the oxygen atoms in the rings of the channel are too large to offer them the same easy charge neutrality available to the potassium ions.

“The simplicity of it all was what struck me most,” MacKinnon says. “All the potassium channels in all the life forms we know have this same structure for the selectivity filter. It was very beautiful and rewarding to see it.”

The significance of MacKinnon's advance was recognized just the next year when he shared the 1999 Albert Lasker Award for Basic Medical Research with two other ion-channel scientists, Bertil Hille, Ph.D., a professor of life sciences at the University of Washington, and Clay M. Armstrong, Ph.D., a professor of physiology at the University of Pennsylvania

“Rod's beautiful X-ray structures give the definitive answer to potassium ion selectivity in ion channels,” says Armstrong. “Selectivity is essential to life, important all the way from bacterial survival to electrical signaling in the nervous system.” So fundamental are potassium channels to life, in fact, that MacKinnon's discoveries may lead to new treatments for neurological, cardiac, and muscular disorders.

More recently, MacKinnon has discovered the structures of other channels and channel components, extending his insights. In the May 1, 2003, issue of Nature, he reported the atomic structure of a potassium channel's voltage-sensing gate, which is responsible for opening and closing the channel. Where the selectivity filter controls which ions may pass through the channel, the gate controls when they may pass.

Reflecting on his own path, MacKinnon advises young scientists not to fear moving into new areas where they may feel uncertain of themselves.

“It's very comforting to be an expert,” he says. “But you'll do better if you push your limits of competence. Teach yourself new things and just do them.”

Mackinnon's oral history was conducted by the Oral History and Archives Project for the Pew Scholars Program in the Biomedical Sciences, supported by the Trusts through a grant to the University of California at Los Angeles.

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